Toward Potent Ghrelin Receptor Ligands Based on Trisubstituted 1,2,4-Triazole Structure. 2. Synthesis and Pharmacological in Vitro and in Vivo Evaluations

• Published in: Journal of medicinal chemistry Vol. 50; no. 23; pp. 5790 - 5806
• Main Authors: Moulin, Aline, Demange, Luc, Bergé, Gilbert, Gagne, Didier, Ryan, Joanne, Mousseaux, Delphine, Heitz, Annie, Perrissoud, Daniel, Locatelli, Vittorio, Torsello, Antonio, Galleyrand, Jean-Claude, Fehrentz, Jean-Alain, Martinez, Jean
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.11.2007; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Calcium - metabolism; Cell Line; Chemical Sciences; Chemistry, Medicinal; Cricetinae; Eating - drug effects; Growth Hormone - secretion; Hormones. Endocrine system; Humans; Life Sciences & Biomedicine; Ligands; Male; Medical sciences; Oligopeptides - pharmacology; Organic chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin - agonists; Receptors, Ghrelin - antagonists & inhibitors; Recombinant Proteins - agonists; Recombinant Proteins - antagonists & inhibitors; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; GROWTH-HORMONE; Rat; Ligand; Somatotropin releasing factor; Rodentia; Ghrelin receptor; In vitro; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Food intake; Animal; Piperidine derivatives; Carboxamide; Indole derivatives; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0704550

A series of ghrelin receptor ligands based on the trisubstituted 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and biological activity. In this study, we explored the significance of the aminoisobutyryl (Aib) moiety, a common feature in numerous growth hormone secretagogues described in the literature. Potent agonist and antagonist ligands of the growth hormone secretagogue receptor type 1a (GHS-R1a) were obtained, i.e., compounds 41 (JMV2894) and 17 (JMV3031). The best compounds were evaluated for their in vivo activity on food intake, after sc injection in rodents. Among the tested compounds, few of them were able to stimulate food intake and some others, i.e., compounds 4 (JMV2959), 17, and 52 (JMV3021), acted as potent in vivo antagonist of hexarelin-stimulated food intake. These compounds did not stimulate growth hormone secretion in rats and furthermore did not antagonize growth hormone secretion induced by hexarelin, revealing that it is possible to modulate food intake without altering growth hormone secretion.